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Catherine Bollard

Engineering TGFB receptor to enhance NK cells and fight neuroblastoma

Catherine Bollard

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Catherine Bollard, M.B.Ch.B., M.D.

Catherine Bollard, M.B.Ch.B., M.D., and her research team published results showing potential efficacy of a novel cell therapeutic for treatment of pediatric patients with relapsed/refractory neuroblastoma.

The research paper, entitled, “Engineering the TGFβ receptor to Enhance the Therapeutic Potential of Natural Killer Cell as an Immunotherapy for Neuroblastoma,” was published on April 29, 2019 by Clinical Cancer Research and is being recognized for the potential efficacy of the “off the shelf” treatment for patients with relapsed/refractory neuroblastoma.

The researcher’s approach allows them to manipulate Natural Killer (NK) cells, expand and reinfuse them within a patient so they can fight cancer and disease.

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Dr. Bollard, who is the senior corresponding author of the study and director of the Center for Cancer and Immunology Research at the Children’s Research Institute. “In other words, turning the negative effects of TGFb into positive effects enhances the persistence and anti-tumor activity of these tumor-killing NK cells in vivo.”

NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of human leukocyte antigen (HLA) expression on interacting target cells, as in the case for a majority of solid tumors, including neuroblastoma. With neuroblastoma being a leading cause of pediatric cancer-related deaths, it presents as an ideal candidate for NK cell therapy.

“This manuscript encompasses a significant portion of work, in which we generated genetically-modified NK cells as an enhanced form of immunotherapy for neuroblastoma,” said Rachel Burga, Ph.D., lead author and graduate of the Institute for Biomedical Sciences at George Washington and Children’s National Health System.  “We’re very excited to share our pre-clinical findings which demonstrate the efficacy of approaches to “hijack” the TGFb receptor and target TGFb in the tumor microenvironment.”

She added that the approach will allow for the NK cells to simultaneously resist the immune suppression in the microenvironment and initiate activation to increase their ability to target tumor cells.

Pre-clinical testing and research for this trial began in 2016 and ended in 2019. “The idea came from a Department of Defense award given to Dr. Bollard and Dr. Cruz and they took the idea and reduced it to practice and showed feasibility for pre-clinical trial,” said Rohan Fernandes, Ph.D., assistant professor in the Department of Medicine at George Washington University and senior author on the manuscript.

Fernandes added that the timeframe to start the clinical trial is within the next two to four years at Children’s National.

Additional authors include Rachel A. Burga, Ph.D., Eric Yvon, Rohan Fernandes, Conrad Russell Cruz, and Catherine M. Bollard, M.B.Ch.B., M.D.

Girl using smartphone with dad

Children’s National to participate in Hackathon

Girl using smartphone with dad

On March 24, 2019, George Washington University will host their annual George Hacks Medical Hackathon. Among the participants are Seema Khan, M.D., a gastroenterologist, and Kelley Shirron, MSN, CPNP, a nurse practitioner, at Children’s National Health System.

The event is a 24-hour innovation competition at George Washington University that will feature pitches addressing needs for patients battling cancer, medical and social innovation solutions for the aging community and more.

Below, Seema Khan and Kelley Shirron provide insight about the My EoE and BearScope mobile app they are pitching for the competition:

What is the idea surrounding the mobile app you are developing?

We encounter a lot of cases where the patient diagnosis of eosinophilic esophagitis (EoE) and its follow up care are delayed due to a lack of understanding regarding the nature of symptoms, miscommunications related to type of treatment and scheduling as a whole. From the moment the patient visits the doctor to the point of when an endoscopy is scheduled, the process warrants improvement and we believe this mobile app can assist tremendously. The availability of a mobile app like this can make it easier for patients to have better preparation for their procedures.

What are some obstacles that you encounter in relation to endoscopies?

We often experience instances where patients inadvertently violate their NPO (nothing by mouth) order, which results in complete cancellation of their endoscopy procedure. In a case like this, the patient would have to wait another few weeks before they can reschedule an appointment. An NPO violation leads to wasted resources. Mom and Dad took off work, the patient missed school, experienced unnecessary fasting and now they have to do it all over again, resulting in a delay of diagnosis.

How will the mobile app help patients with these issues?

We would like for the mobile app to allow patients to monitor their symptoms, corresponding to their period of treatment. The treatment for our patients is a very important process which requires close adherence. For example, the treatment can be tricky because it resembles the same diet that many kids with food allergies have to adhere to. With this mobile app, the patient could have easy access to that information and identify their food avoidances. The mobile app would identify foods they should avoid in their diet and the seasons they should avoid for scheduling of their scopes due to known seasonal allergies.

How do you envision your patients personally benefitting from the device?

We believe our mobile app can help patients avoid unnecessary pitfalls. For example, the mobile app can incorporate a game or an alarm to remind the patient to drink water or to take their medicine when necessary. A notification can pop up to remind the patient to stop eating and drinking and can detail what that means. Those notifications also include alerts for no gum chewing, hard candies, drinking coffee, etc.

Sometimes patients accidently go to the wrong location. It’s really heartbreaking to experience that because in some cases the patient hasn’t eaten in eight to 12 hours. Many times they’ve endured the pre -colonoscopy “clean out” for those also undergoing a colonoscopy and now we have to reschedule their procedure, all because of a location mix-up. We’re thinking of ways to integrate with WAZE or other navigational apps into this application to help patients coordinate their routes better, which is a helpful feature to have in Washington, D.C. An address of their procedure location could be pre-entered into the mobile app by their provider to avoid location mix-ups. By incorporating this feature, it will help us provide patients with efficient and prompt care.

What excites you about this project?

We’re excited about this because this mobile app could improve the delivery of health care by helping patients and their families identify possible associations between their diet and their symptoms. The content in the app will also help them be better prepared for their diagnostic procedure, and will hopefully reduce last-minute cancellations due to misunderstandings. These capabilities are fun to think about and we’re excited about the creativity that will be incorporated into this project.

Children’s National will also be hosting the 2019 Clinical and Translational Science Institute (CTSI) Healthcare Hackathon on March 29th. The half day hackathon will feature both medical and public health applications developed by participating teams. More information about the event can be found on the event’s official website. To register you team, please click here.  

Nikki Gillum Posnack

Examining BPA’s impact on developing heart cells

Nikki Gillum Posnack

“We know that once this chemical enters the body, it can be bioactive and therefore can influence how heart cells function,” says Nikki Gillum Posnack, Ph.D. “This is the first study to look at the impact BPA exposure can have on heart cells that are still developing.”

More than 8 million pounds of bisphenol A (BPA), a common chemical used in manufacturing plastics, is produced each year for consumer goods and medical products. This endocrine disruptor reaches 90 percent of the population, and excessive exposure to BPA, e.g., plastic bottles, cash register receipts, and even deodorant, is associated with adverse cardiovascular events that range from heart arrhythmias and angina to atherosclerosis, the leading cause of death in the U.S.

To examine the impact BPA could have in children, researchers with Children’s National Heart Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation evaluated the short-term risks of BPA exposure in a preclinical setting. This experimental research finds developing heart cells respond to short-term BPA exposure with slowed heart rates, irregular heart rhythms and calcium instabilities.

While more research is needed to provide clinical recommendations, this preclinical model paves the way for future study designs to see if young patients exposed to BPA from medical devices or surgical procedures have adverse cardiac events and altered cardiac function.

“Existing research explores the impact endocrine disruptors, specifically BPA, have on adults and their cardiovascular and kidney function,” notes Nikki Gillum Posnack, Ph.D., a study author and assistant professor at Children’s National and The George Washington University. “We know that once this chemical enters the body, it can be bioactive and therefore can influence how heart cells function. This is the first study to look at the impact BPA exposure can have on heart cells that are still developing.”

The significance of this research is that plastics have revolutionized the way clinicians and surgeons treat young patients, especially patients with compromised immune or cardiac function.

Implications of Dr. Posnack’s future research may incentivize the development of alternative products used by medical device manufacturers and encourage the research community to study the impact of plastics on sensitive patient populations.

“It’s too early to tell how this research will impact the development of medical devices and equipment used in intensive care settings,” notes Dr. Posnack. “We do not want to interfere with clinical treatments, but, as scientists, we are curious about how medical products and materials can be improved. We are extending this research right now by examining the impact of short-term BPA exposure on human heart cells, which are developed from stem cells.”

This research, which appears as an online advance in Nature’s Scientific Reports, was supported by the National Institutes of Health under awards R00ES023477, RO1HL139472 and UL1TR000075, Children’s Research Institute and the Children’s National Heart Institute. NVIDIA Corporation provided GPUs, computational devices, for this study.